Ocular hydrogel tyrosine kinase inhibitor implants

Abstract

Provided herein are sustained-release biodegradable ocular hydrogel implants which are useful in the treatment of certain ocular conditions.

1 . A system comprising (i) a sustained-release biodegradable ocular hydrogel implant comprising a tyrosine kinase inhibitor and a polymer network, wherein the ocular hydrogel implant after ocular administration comprises and a clearance zone, wherein the clearance zone is devoid of undissolved TKI particles prior to release of the TKI and (ii) a needle that is tipped with annealed polyethylene glycol, wherein the implant is loaded into the needle. 
     
     
         2 . The system of  claim 1 , wherein the ocular hydrogel implant is in the form of a cut strand prior to administration. 
     
     
         3 . The system of  claim 1 , wherein the dissolved TKI is present in the hydrogel implant at or near its saturation level. 
     
     
         4 . The system of  claim 1 , wherein the size of the clearance zone increases as a function of the amount of TKI release. 
     
     
         5 . The system  claim 1 , wherein the ocular hydrogel implant is fully degraded following release of at least 90% of the TKI. 
     
     
         6 . The system  claim 1 , wherein the ocular hydrogel implant is fully degraded after about 3 months following complete release of the TKI. 
     
     
         7 . The system of  claim 1 , wherein degradation of the ocular hydrogel occurs prior to release of the TKI. 
     
     
         8 . The system of  claim 1 , wherein the polymer network comprises a plurality of polyethylene glycol (PEG) units. 
     
     
         9 . The system of  claim 1 , wherein the polymer network comprises a plurality of multi-arm PEG units. 
     
     
         10 . The system of  claim 1 , wherein the polymer network comprises a plurality of 4- or 8-arm PEG units. 
     
     
         11 . The system of  claim 1 , wherein the polymer network comprises a plurality of PEG units having the formula: 
       
         
           
           
               
               
           
         
       
       wherein n represents an ethylene oxide repeating unit and the wavy lines represent the points of repeating units of the polymer network. 
     
     
         12 . The system of  claim 1 , wherein the polymer network is formed by reacting a plurality of polyethylene glycol (PEG) units selected from 4a20K PEG SAZ, 4a20K PEG SAP, 4a20K PEG SG, 4a20K PEG SS, 8a20K PEG SAZ, 8a20K PEG SAP, 8a20K PEG SG, and 8a20K PEG SS with one or more PEG or Lysine based-amine groups selected from 4a20K PEG NH2, 8a20K PEG NH2, and trilysine, or a salt thereof. 
     
     
         13 - 15 . (canceled) 
     
     
         16 . The system of  claim 1 , wherein the tyrosine kinase inhibitor is homogenously dispersed within the polymer network. 
     
     
         17 . The system of  claim 1 , wherein the tyrosine kinase inhibitor is released over a period of at least 15 days. 
     
     
         18 . The system of  claim 1 , wherein the tyrosine kinase inhibitor is released over a period of at least 30 days. 
     
     
         19 . The system of  claim 1 , wherein the tyrosine kinase inhibitor is released over a period of at least 60 days. 
     
     
         20 . The system  claim 1 , wherein the tyrosine kinase inhibitor is released over a period of at least 90 days. 
     
     
         21 - 24 . (canceled) 
     
     
         25 . The system of  claim 1 , wherein the tyrosine kinase inhibitor is selected from abemaciclib, acalabrutinib, afatinib, alectinib, axitinib, barictinib, binimetinib, brigatinib, cabozantinib, ceritinib, coblmetinib, crizotinib, dabrafenib, dacomitinib, dasatinib, encorafenib, erlotinib, everolimus, fostamatinib, gefitinib, gilteritinib, ibrutinib, imatinib, larotrectinib, lenvatinib, lorlatinib, axitinib, idelalisib, lenvatinib, midostaurin, neratinib, netarsudil, nilotinib, nintedanib, osimertinib, palbociclib, pazopanib, ponatinib, regorafenib, ribociclib, ruxolitinib, sirolimus, sorafenib, sunitinib, temsirolimus, tofacitinib, trametinib, vandetanib, and vemurafenib. 
     
     
         26 . The system of  claim 1 , wherein the tyrosine kinase inhibitor is axitinib. 
     
     
         27 . (canceled) 
     
     
         28 . A method of treating an ocular condition in a subject in need thereof, comprising utilizing the system of  claim 1  for injecting or affixing the ocular hydrogel implant to the subject. 
     
     
         29 - 32 . (canceled)